Epigenetic modifications such as histone acetylation and DNA methylation are critical for the long-lasting regulation of gene expression during development and may be a major mechanism of information storage in the brain. Changes in epigenetic modifications occur in animal models of depression and anxiety disorders, and alterations in DNA methylation have been found in post-mortem brains from patients with schizophrenia and bipolar disorder. Defects in epigenetic modifications may contribute to impairments in synaptic plasticity and cognitive function associated with many psychiatric disorders. Our work suggests that epigenetic modifications are a critical component of both synaptic plasticity and memory formation, but the relationship between epigenetic modifications such as histone acetylation and DNA methylation during memory formation is unknown.. The foundation of this work is established by candidate gene studies, but large-scale studies of this novel aspect of memory are needed to define the relationship between different epigenetic modifications and to determine how they relate to gene expression changes. In this application, we propose three Specific Aims to address these issues. In Specific Aim 1, we will examine gene expression, histone acetylation and DNA methylation during memory consolidation and maintenance to define the relationship between changes in histone acetylation and DNA methylation and short-term and long-lasting changes in gene expression after learning. In Specific Aim 2, we will use bi-directional manipulations of histone acetyltransferase and histone deacetylase (HDAC) activity known to affect memory to test the functional consequences of these manipulations on gene expression, histone acetylation and DNA methylation after learning. In Specific Aim 3, we will define the mechanism of HDAC recruitment to target genes during long- term memory formation by examining long-term memory, synaptic plasticity, and gene expression in mice with forebrain-specific deletion of the HDAC targeting protein SIN3A. Together, these experiments will establish the relationship between histone acetylation, DNA methylation, and gene expression during memory formation, as well as test our hypothesis that these epigenetic modifications are linked by SIN3A-containing repressor complexes. Determining the genes marked by epigenetic modifications and the mechanisms that link these modifications to the regulation of gene expression during long-term memory formation and maintenance will provide critical insight into the role of these modifications in memory storage and provide targets for treatment of the cognitive component of psychiatric disorders such as schizophrenia, bipolar disorder, and depression.